Sung Min Han, Kriti Mohan, Anthony Zoghbi, Yong Lin, Claire Haueter, Hiroshi Tsuda, Youfeng Yang, Hugo Bellen, Michael Miller, Yadollah Harati, Justin Kwan, Chao Tong
[
Development & Evolution Meeting,
2008]
The C. elegans MSPs are multi-functional proteins that are abundantly expressed in sperm. MSPs function as intracellular cytoskeletal proteins that drive sperm motility and extracellular signaling proteins. Secreted MSPs bind to the VAB-1 Eph receptor tyrosine kinase expressed on oocytes and ovarian sheath cells to induce oocyte maturation and sheath contraction. C. elegans VPR-1, human VAPB/ALS8, and Drosophila VAP33 are homologous proteins (collectively called VAPs) with an N-terminal MSP domain and a C-terminal transmembrane domain. A missense mutation (P56S) in the VAPB/ALS8 MSP domain is associated with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Here, we report that VAP MSP domains are cleaved from their transmembrane domains and secreted into the extracellular environment, where they directly bind to cell surface Eph receptors and other receptors. We show that VAPs and Eph receptors function in common genetic pathways during C. elegans and Drosophila development. The P56S mutation causes intracellular VAP aggregation and a failure to secrete the MSP domain. Secretion of MSPs and VAP MSP domains is likely unconventional, as these proteins lack signal sequences. Our results show that VAP MSP domains are secreted ligands for Eph receptors, the largest class of receptor tyrosine kinases in the human genome. Furthermore, our studies provide insight into potential mechanisms that may impact the pathogenesis of ALS and SMA.